Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate

Introduction: N-(2-tert-butyl-14 (4,4-difluorocyclohexyl)methyl)-1 H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neurepathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure. Methods: AZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [C-11]pivalate was obtained via C-11-carboxylation of tert-butyl lithium. The target compound, [C-11]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [11C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino-44(4,4-difluorocyclohexlmethylamino)phenylethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey. Results: The overall radiochemical yield of final formulated radiochemically pure (>99%) [C-11]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13 GBq/mu mol at time of administration (58 min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous. Conclusions: AZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure. (C) 2013 Elsevier Inc. All rights reserved.